Progesterone Receptor Membrane Component 1 Regulates Cellular Stress Responses and Inflammatory Pathways in Chronic Neuroinflammatory Conditions.

Alzheimer's disease (AD) is the leading cause of dementia and is one of the neurodegenerative diseases that are caused by neuronal death due to various triggers. Neuroinflammation plays a critical role in the development of AD. The neuroinflammatory response is manifested by pro-inflammatory cytokines, such as interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α; various chemokines; nitrous oxide; and reactive oxygen species. In this study, we evaluated the relevance of progesterone receptor membrane component 1 (PGRMC1), which is expressed in the brain cells during the induction of neuroinflammation. A lipopolysaccharide (LPS)-induced chronic neuroinflammation model and Pgrmc1 knockdown cells were used to assess the inflammatory cytokine levels, AD-related factors, inflammation-related signaling, and cell death. Pgrmc1 knockout (KO) mice had higher IL-1ß levels after treatment with LPS compared with those of wild-type (WT) mice. Furthermore, Pgrmc1 KO mice had higher levels of inflammatory factors, endoplasmic reticulum stress indicators, and AD-associated markers compared with those of WT mice who underwent LPS treatment or not. Finally, these indicators were observed in vitro using U373-MG astrocytes. In conclusion, the loss of PGRMC1 may promote neuroinflammation and lead to AD.

Progesterone increases hepatic lipid content and plasma lipid levels through PR- B-mediated lipogenesis.

Progesterone (P4) is a crucial reproductive hormone that acts as a precursor for all other endogenous steroids. P4 modulates transcriptional activity during reproduction by binding to progesterone receptors (PR). However, the physiological role of P4 in the liver is understudied. P4-mediated lipid metabolism in the liver was investigated in this study, as P4 facilitates insulin resistance and influences energy metabolism. While exogenous lipids are mainly obtained from food, the liver synthesizes endogenous triglycerides and cholesterol from a carbohydrate diet. Hepatic de novo lipogenesis (DNL) is primarily determined by acetyl-CoA and its biosynthetic pathways, which involve fatty acid and cholesterol synthesis. While P4 increased the hepatic levels of sterol regulatory element-binding protein 1 C (SREBP-1 C), peroxisome proliferator-activated receptor-gamma (PPARγ), acetyl-CoA carboxylase (ACC), and CD36, co-treatment with the P4 receptor antagonist RU486 blocked these proteins and P4-mediated lipogenesis. RNA sequencing was used to assess the role of P4 in lipogenic events, such as fatty liver and fatty acid metabolism, lipoprotein signaling, and cholesterol metabolism. P4 induced hepatic DNL and lipid anabolism were confirmed in the liver of ovarian resection mice fed a high-fat diet or in pregnant mice. P4 increased lipogenesis directly in mice exposed to P4 and indirectly in fetuses exposed to maternal P4. The lipid balance between lipogenesis and lipolysis determines fat build-up and is linked to lipid metabolism dysfunction, which involves the breakdown and storage of fats for energy and the synthesis of structural and functional lipids. Therefore, P4 may impact the lipid metabolism and reproductive development during gestation.

PIBF1 regulates trophoblast syncytialization and promotes cardiovascular development.

Proper placental development in early pregnancy ensures a positive outcome later on. The developmental relationship between the placenta and embryonic organs, such as the heart, is crucial for a normal pregnancy. However, the mechanism through which the placenta influences the development of embryonic organs remains unclear. Trophoblasts fuse to form multinucleated syncytiotrophoblasts (SynT), which primarily make up the placental materno-fetal interface. We discovered that endogenous progesterone immunomodulatory binding factor 1 (PIBF1) is vital for trophoblast differentiation and fusion into SynT in humans and mice. PIBF1 facilitates communication between SynT and adjacent vascular cells, promoting vascular network development in the primary placenta. This process affected the early development of the embryonic cardiovascular system in mice. Moreover, in vitro experiments showed that PIBF1 promotes the development of cardiovascular characteristics in heart organoids. Our findings show how SynTs organize the barrier and imply their possible roles in supporting embryogenesis, including cardiovascular development. SynT-derived factors and SynT within the placenta may play critical roles in ensuring proper organogenesis of other organs in the embryo.

TXNIP in liver sinusoidal endothelial cells ameliorates alcohol-associated liver disease via nitric oxide production.

Dysregulation of liver sinusoidal endothelial cell (LSEC) differentiation and function has been reported in alcohol-associated liver disease (ALD). Impaired nitric oxide (NO) production stimulates LSEC capillarization and dysfunction; however, the mechanism underlying NO production remains unclear. Here, we investigated the role of thioredoxin-interacting protein (TXNIP), an important regulator of redox homeostasis, in endothelial cell NO production and its subsequent effects on ALD progression. We found that hepatic TXNIP expression was upregulated in patients with ALD and in ethanol diet-fed mice with high expression in LSECs. Endothelial cell-specific Txnip deficiency (TxnipΔEC) in mice exacerbated alcohol-induced liver injury, inflammation, fibrosis, and hepatocellular carcinoma development. Deletion of Txnip in LSECs led to sinusoidal capillarization, downregulation of NO production, and increased release of proinflammatory cytokines and adhesion molecules, whereas TXNIP overexpression had the opposite effects. Mechanistically, TXNIP interacted with transforming growth factor ß-activated kinase 1 (TAK1) and subsequently suppressed the TAK1 pathway. Inhibition of TAK1 activation restored NO production and decreased the levels of proinflammatory cytokines, thereby, blocking liver injury and inflammation in TxnipΔEC mice. Our findings indicate that upregulated TXNIP expression in LSECs serves a protective role in ameliorating ALD. Enhancing TXNIP expression could, therefore, be a potential therapeutic approach for ALD.

Various Endoscopic Approaches for Removal of Proventricular Foreign Bodies in Parrots-Three Case Reports.

Although the use of incision-free endoscopy for foreign body (FB) removal in dogs and cats has been extensively documented, its application in birds remains limited. Thus, we present the endoscopic removal of gastrointestinal (GI) FBs from psittacine birds, employing different patient positioning and anesthesia methods. Two blue-and-yellow macaws (Ara ararauna) and a Triton cockatoo (Cacatua galerita triton) were examined. X-ray imaging revealed FBs situated in the proventriculus in each case. The FBs, all identified as feeding tubes, were safely removed using grasping forceps during the endoscopic procedure, and no severe complications occurred. Based on the outcomes of each operation, the most suitable patient position may be ventral recumbency rather than dorsal recumbency, with the use of a mask or endotracheal intubation, depending on the anticipated operation time. However, a larger number of cases would be necessary to confirm the optimal patient positioning and anesthesia method.

Effects of prenatal bisphenol S and bisphenol F exposure on behavior of offspring mice.

Bisphenol A (BPA) is a representative endocrine-disrupting chemical that exhibits hormonal disturbance reactions. Various alternatives, such as Bisphenol S (BPS) and Bisphenol F (BPF), are being developed. BPS and BPF (which are representative alternatives to BPA) are used in consumer products such as polycarbonate plastics and epoxy resins. They have structures similar to those of BPA and have also been proven to be exogenous endocrine disruptors. However, although there are many studies on BPA, there are few studies on the neurodevelopmental effects of BPS and BPF. Therefore, in this study, we analyzed neurobehavioral changes in offspring mice exposed to BPS and BPF during brain development by administering BPS and BPF to pregnant mice. We found that prenatal exposure to BPS and BPF did not affect anxiety-and depression-like behaviors, locomotion, sociability, memory, or cognition functions in offspring mice. However, exposure to BPS and BPF decreased the preference for social novelty in the offspring mice. Taken together, these findings suggest that perinatal exposure to BPS and BPF affects changes in social behaviors, but not other behavioral changes such as emotion, memory, or cognition in the offspring mice.

Curcumae radix Reduces Endoplasmic Reticulum Stress in Mice with Chronic Neuroinflammation.

Endoplasmic reticulum (ER) stress is a condition in which the ER protein-folding machinery is impaired, leading to the accumulation of improperly folded proteins and triggering an unfolded-protein response. Excessive ER stress causes cell death and contributes to the development of chronic diseases. Interestingly, there is a bidirectional relationship between ER stress and the nuclear factor-kappa B (NF-κB) pathway. Curcumin, a natural polyphenolic compound found in Curcumae radix, exerts its neuroprotective effects by regulating ER stress and inflammation. Therefore, investigating the potential protective and regulatory effects of curcumin on ER stress, inflammation, and neurodegeneration under chronic neuroinflammatory conditions is of great interest. Mice were pretreated with Curcumae radix extract (CRE) for 19 days and then treated with CRE plus lipopolysaccharide for 1 week. We monitored pro-inflammatory cytokine levels in the serum and ER stress-, inflammation-, and neurodegeneration-related markers in the mouse cerebrum and hippocampus using Western blotting and qRT-PCR. CRE reduced Interleukin-1 beta levels in the blood and brain of mice with lipopolysaccharide-induced chronic inflammation. CRE also suppressed the expression of markers related to the ER stress and NF-κB signaling pathways. The expression of neurodegeneration-related markers was reduced in the mouse cerebrum and hippocampus. CRE exerts neuroprotective effects under chronic inflammatory conditions via multifaceted anti-inflammatory and ER stress-pathway regulatory mechanisms.

Regulation of uterus and placenta remodeling under high estradiol levels in gestational diabetes mellitus models†.

The present study aimed to investigate the regulation of placentas and uterus remodeling and involvement of estradiol in gestational diabetes mellitus. To achieve this, we established in vitro and in vivo models for gestational diabetes mellitus placentas by culturing human placental choriocarcinoma cells (BeWo) under hyperglycemic concentration and treating pregnant rats with streptozotocin. We evaluated the expression of angiogenesis-related proteins. The expression of the anti-angiogenic factor, excess placental soluble fms-like tyrosine kinase 1 was increased in our in vitro gestational diabetes mellitus model compared with the control. Moreover, the expressions of placental soluble fms-like tyrosine kinase 1 and the von Willebrand factor were also significantly elevated in the placenta of streptozotocin-treated rats. These data indicate the disruption of angiogenesis in the gestational diabetes mellitus placentas. The expression levels of connexin 43, a component of the gap junction and collagen type I alpha 2 chain, a component of the extracellular matrix, were decreased in the gestational diabetes mellitus uterus. These results suggest that uterus decidualization and placental angiogenesis are inhibited in gestational diabetes mellitus rats. Our results also showed upregulation of the expression of genes regulating estradiol synthesis as well as estrogen receptors in vivo models. Accordingly, the concentration of estradiol measured in the culture medium under hyperglycemic conditions, as well as in the serum and placenta of the streptozotocin-treated rats, was significantly elevated compared with the control groups. These results suggest that the dysregulated remodeling of the placenta and uterus may result in the elevation of estradiol and its signaling pathway in the gestational diabetes mellitus animal model to maintain pregnancy.

Hepatic progesterone receptor membrane component 1 attenuates ethanol-induced liver injury by reducing acetaldehyde production and oxidative stress.

Alcohol-associated liver disease (ALD) is caused by excessive abuse of alcohol. One of the most representative causes of ALD is the action of acetaldehyde. Acetaldehyde is a toxic material produced when alcohol is metabolized through some enzymes, and it causes endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and tissue injury. In this study, we assessed the relationship between Progesterone receptor membrane component 1 (PGRMC1) and ALD because PGRMC1 is expressed in the ER and mitochondria in the liver. Using the chronic and binge alcohol feeding models, we assessed acetaldehyde level, liver damage, alcohol-degrading enzymes, and ER stress. Compared with wild-type (WT) mice ethanol-fed Pgrmc1 knockout (KO) mice had higher levels of alanine aminotransferase (ALT) and alcohol-degrading enzymes, and Pgrmc1 KO mice had high serum acetaldehyde and ER stress levels compared with WT mice with control and ethanol feeding. Loss of Pgrmc1 increased acetaldehyde production through increased expression of alcohol dehydrogenase and catalase, which led to increased ER stress and suggested that cell death was promoted. In conclusion, it has been proposed that the loss of PGRMC1 could promote ALD and cause liver damage in alcohol-abusing humans.NEW & NOTEWORTHY Loss of Pgrmc1 increased acetaldehyde production, and excess acetaldehyde consequently increased ER stress, which activates apoptosis. Since low expression of PGRMC1 is vulnerable to alcoholic liver damage, the loss of PGRMC1 expression may increase susceptibility to ALD.

Neuroprotective Effects of Ecklonia cava in a Chronic Neuroinflammatory Disease Model.

Inflammation is a natural defense mechanism against noxious stimuli, but chronic inflammation can lead to various chronic diseases. Neuroinflammation in the central nervous system plays an important role in the development and progression of neurodegenerative diseases. Polyphenol-rich natural products, such as Ecklonia cava (E. cava), are known to have anti-inflammatory and antioxidant properties and can provide treatment strategies for neurodegenerative diseases by controlling neuroinflammation. We investigated the effects of an E. cava extract on neuroinflammation and neurodegeneration under chronic inflammatory conditions. Mice were pretreated with E. cava extract for 19 days and then exposed to E. cava with lipopolysaccharide (LPS) for 1 week. We monitored pro-inflammatory cytokines levels in the serum, inflammation-related markers, and neurodegenerative markers using Western blotting and qRT-PCR in the mouse cerebrum and hippocampus. E. cava reduced pro-inflammatory cytokine levels in the blood and brain of mice with LPS-induced chronic inflammation. We also measured the activity of genes related to neuroinflammation and neurodegeneration. Surprisingly, E. cava decreased the activity of markers associated with inflammation (NF-kB and STAT3) and a neurodegenerative disease marker (glial fibrillary acidic protein, beta-amyloid) in the cerebrum and hippocampus of mice. We suggest that E. cava extract has the potential as a protective agent against neuroinflammation and neurodegenerative diseases.

Dietary supplementation with nicotinamide riboside improves fetal growth under hypoglycemia.

Nicotinamide riboside (NR) is considered a super-supplement that prevents obesity and diabetes. While NR has been investigated for various effects depending on nutritional conditions, metabolic research on women and pregnant women has rarely been discussed. In this study, we focused on the glycemic control of NR in females and found the protective role of NR in pregnant animals under hypoglycemic conditions. Metabolic-tolerance tests were performed in vivo under progesterone (P4) exposure after ovariectomy (OVX). NR enhanced resistance to energy deprivation and showed a slight increase in gluconeogenesis in naïve control mice. However, NR reduced hyperglycemia and significantly induced gluconeogenesis in OVX mice. While NR reduced hyperglycemia in the P4-treated OVX mice, it reduced insulin response and substantially increased gluconeogenesis. Similar to animal experiments, NR increased gluconeogenesis and mitochondrial respiration in Hep3B cells. The gluconeogenic function of NR is mediated by tricarboxylic acid cycle (TCA) cycle enrichment, as residual pyruvate could induce gluconeogenesis. NR recovered fetal growth by increasing blood glucose levels when hypoglycemia was induced by diet-restriction during pregnancy. Our study revealed the glucose-metabolic function of NR in hypoglycemic pregnant animals, suggesting NR as a dietary supplement to improve fetal growth. Because diabetic women suffer from hypoglycemia due to insulin therapy, NR has therapeutic potential for use as a glycemic control pill.

PGRMC1 Ablation Protects from Energy-Starved Heart Failure by Promoting Fatty Acid/Pyruvate Oxidation.

Heart failure (HF) is an emerging epidemic with a high mortality rate. Apart from conventional treatment methods, such as surgery or use of vasodilation drugs, metabolic therapy has been suggested as a new therapeutic strategy. The heart relies on fatty acid oxidation and glucose (pyruvate) oxidation for ATP-mediated contractility; the former meets most of the energy requirement, but the latter is more efficient. Inhibition of fatty acid oxidation leads to the induction of pyruvate oxidation and provides cardioprotection to failing energy-starved hearts. One of the non-canonical types of sex hormone receptors, progesterone receptor membrane component 1 (Pgrmc1), is a non-genomic progesterone receptor associated with reproduction and fertility. Recent studies revealed that Pgrmc1 regulates glucose and fatty acid synthesis. Notably, Pgrmc1 has also been associated with diabetic cardiomyopathy, as it reduces lipid-mediated toxicity and delays cardiac injury. However, the mechanism by which Pgrmc1 influences the energy-starved failing heart remains unknown. In this study, we found that loss of Pgrmc1 inhibited glycolysis and increased fatty acid/pyruvate oxidation, which is directly associated with ATP production, in starved hearts. Loss of Pgrmc1 during starvation activated the phosphorylation of AMP-activated protein kinase, which induced cardiac ATP production. Pgrmc1 loss increased the cellular respiration of cardiomyocytes under low-glucose conditions. In isoproterenol-induced cardiac injury, Pgrmc1 knockout resulted in less fibrosis and low heart failure marker expression. In summary, our results revealed that Pgrmc1 ablation in energy-deficit conditions increases fatty acid/pyruvate oxidation to protect against cardiac damage via energy starvation. Moreover, Pgrmc1 may be a regulator of cardiac metabolism that switches the dominance of glucose-fatty acid usage according to nutritional status and nutrient availability in the heart.

GLUT4 degradation by GLUTFOURINH® in mice resembles moderate-obese diabetes of human with hyperglycemia and low lipid accumulation.

BACKGROUNDS AND AIMS: Type 2 diabetes mellitus (T2D) is a chronic disease characterized by insulin resistance and hyperglycemia. To investigate T2D, genetic and chemical induced hyper-obese rodent models have been experimentally developed. However, establishment of moderate-obese diabetes model will confer diverse opportunities for translational studies. In this study, we found the chemical, GLUTFOURINH® (GFI), induces post-translational degradation of glucose transporter 4 (GLUT4). We aimed to establish novel diabetic model by using GFI. METHODS AND RESULTS: Low plasma membrane GLUT4 (pmGLUT4) levels by GFI resulted in reduction of intracellular glucose uptake and TG, and increase of intracellular FFA in A204 cells. Likewise, GFI treatment decreased intracellular TG and increased intracellular FFA levels in Hep3B and 3T3-L1 cells. Mice were administered with GFI (16 mg/kg) for short-term (3-day) and long-term (28- and 31-day) to compared with vehicle injection, HFD model, and T2D model, respectively. Short-term and long-term GFI treatments induced hyperglycemia and hyperinsulinemia with low pmGLUT4 levels. Compared to HFD model, long-term GFI with HFD reduced adipose weight and intracellular TG accumulation, but increased plasma FFA. GFI treatment resulted in insulin resistance by showing low QUICKI and high HOMA-IR values, and low insulin response during insulin tolerance test. Additionally, low pmGLUT4 by GFI heightened hyperglycemia, hyperinsulinemia, and insulin resistance compared to T2D model. CONCLUSIONS: In summary, we report GLUT4 degradation by novel chemical (GFI) induces moderate-obese diabetes representing hyperglycemia, insulin resistance and low intracellular lipid accumulation. The GLUT4 degradation by GFI has translational value for studying diseases related to moderate-obese diabetes.

Alaria alata (Digenea: Diplostomidae) from Korean Raccoon Dog, Nyctereutes procyonoides koreensis, in Korea.

We report a species of diplostomid fluke recovered from 3 carcasses of wild Korean raccoon dog, Nyctereutes procyonoides koreensis, in Korea. A total of 107 diplostomid flukes were recovered from the small intestines of Korean raccoon dogs, which were obtained from the Gangwon Wildlife Medical Rescue Center. Worms fixed with 10% neutral formalin were subjected to microscopic observation and those fixed in 70% ethanol were used for molecular genomic analysis. The worm was divided into 2 separate parts, forebody and hindbody, with a total length of 3,020-4,090 (3,855) µm and a width of 1,210-1,770 (1,562) µm. The boat-shaped forebody has a pair of characteristic tentacular appendage, 2 suckers, holdfast organ, and vitelline follicles. The oval to cylindrical hindbody has reproductive organs. The ovary was round or elliptical and located in the anterior of the testes. Two large testes were slightly segmented and tandemly arranged, occupying almost half of hindbody. The short uterus contained a relatively small number of unembryonated eggs sized 130-140×85-96 µm. The partial sequence of 18S rRNA of this fluke was consistent with Alaria alata. Based on the morphological and molecular characteristics, the diplostomid flukes recovered from the small intestine of Korean raccoon dogs were identified as A. alata (Digenea: Diplostomidae).

The Improvement Effect of D-Chiro-Inositol and Ecklonia cava K. in the Rat Model of Polycystic Ovarian Syndrome.

Introduction: Polycystic Ovarian Syndrome (PCOS) is known to be an endocrine state that is characterized by oligomenorrhea, hyperandrogenism, and highly cystic follicles in the ovaries. The use of food ingredients and traditional medicine in Asian countries is well known, and previous studies have shown that Ecklonia cava K. [Alariaceae] (EC) is able to alleviate PCOS symptoms. D-Chiro-inositol (DCI) administration in pathologies where steroid biosynthesis is a crucial factor, i.e., PCOS, has provided satisfactory results. Methods: Therefore, we studied the synergistic effects of the two previously known active compounds. In rats with letrozole-induced PCOS, we focused on alternative therapies using EC and/or DCI extracts to alleviate ovarian failure. Results: As a nonsteroidal aromatase inhibitor, letrozole inhibits the conversion of testosterone to estrogen and subsequently causes PCOS. We divided 6-week-old female mice into the following six groups and evaluated them: vehicle, PCOS, PCOS + MET (metformin), PCOS + DCI, PCOS + EC, and PCOS + DCI + EC. In our study, PCOS rats treated with EC and DCI had low serum LH and T levels and low serum levels of inflammatory cytokines such as TNFα and IL-6. These treatments also appeared to regulate the production of factors that affect follicle formation and inflammation in the ovaries. Conclusion: We concluded that EC extract and/or DCI administration influenced aromatase production and reduced LH and T stimulation, and cotreatment with EC and DCI consequently restored ovarian dysfunction or anti-inflammatory responses in rats with PCOS-like symptoms.

Porcine Epidemic Diarrhea Virus Infection Induces Autophagosome Formation but Inhibits Autolysosome Formation during Replication.

In this study, we investigated the correlation between the mechanism involved in porcine epidemic diarrhea virus (PEDV) replication and autophagic flux. In this study, we found that as PEDV replicated, production of LC3-II was significantly induced up to 24 h post-infection (hpi). Interestingly, although there was significant production of LC3-II, greater p62 accumulation was simultaneously found. Pretreatment with rapamycin significantly induced PEDV replication, but autolysosome formation was reduced. These results were confirmed by the evaluation of ATG5/ATG12 and LAMP1/LAMP2. Taken together, we conclude that PEDV infection induces autophagosome formation but inhibits autolysosome formation during replication.

Curcumae Radix Decreases Neurodegenerative Markers through Glycolysis Decrease and TCA Cycle Activation.

Neurodegenerative diseases (ND) are being increasingly studied owing to the increasing proportion of the aging population. Several potential compounds are examined to prevent neurodegenerative diseases, including Curcumae radix, which is known to be beneficial for inflammatory conditions, metabolic syndrome, and various types of pain. However, it is not well studied, and its influence on energy metabolism in ND is unclear. We focused on the relationship between ND and energy metabolism using Curcumae radix extract (CRE) in cells and animal models. We monitored neurodegenerative markers and metabolic indicators using Western blotting and qRT-PCR and then assessed cellular glycolysis and metabolic flux assays. The levels of Alzheimer's disease-related markers in mouse brains were reduced after treatment with the CRE. We confirmed that neurodegenerative markers decreased in the cerebrum and brain tumor cells following low endoplasmic reticulum (ER) stress markers. Furthermore, glycolysis related genes and the extracellular acidification rate decreased after treatment with the CRE. Interestingly, we found that the CRE exposed mouse brain and cells had increased mitochondrial Tricarboxylic acid (TCA) cycle and Oxidative phosphorylation (OXPHOS) related genes in the CRE group. Curcumae radix may act as a metabolic modulator of brain health and help treat and prevent ND involving mitochondrial dysfunction.

The aqueous fraction of Castanea crenata inner shell extract reduces obesity and intramuscular lipid accumulation via induction of mitochondrial respiration and fatty acid oxidation in muscle.

BACKGROUND: Skeletal muscle is responsible for free fatty acid (FFA) disposal via mitochondrial respiration and fatty acid oxidation (FAO). Obesity triggers high levels of circulating FFAs, which can cause intramuscular lipid (IMCL) deposition. Diverse phytochemicals, including crude Castanea crenata inner shell extract (CCE), have been shown to possess an anti-obesity effect. PURPOSE: We aimed to demonstrate whether the aqueous fraction of CCE (ACCE) provides an anti-obesity effect with a decrease in plasma FFAs and reduces IMCL. METHODS: High-fat-fed C57BL/6 mice received ACCE via water intake. A204 cells incubated with fatty acids were treated with ACCE. Lipid accumulation and mitochondrial metabolism were assessed using histological and molecular techniques. RESULTS: ACCE possessed a notably higher gallic acid content than CCE among the constituents. ACCE-administered mice exhibited reduced plasma FFA levels, adiposity, and IMCL. Muscle lipotoxicity was suppressed, including apoptosis, ER stress, and inflammation. The anti-lipid effect of ACCE was observed with the induction of mitochondrial respiration and fatty acid oxidation in muscle. CONCLUSIONS: ACCE increases mitochondrial respiration and FAO in skeletal muscle and protects muscle from IMCL and lipotoxicity, reducing plasma FFA and adiposity.

Letrozole Accelerates Metabolic Remodeling through Activation of Glycolysis in Cardiomyocytes: A Role beyond Hormone Regulation.

Estrogen receptor-positive (ER+) breast cancer patients are recommended hormone therapy as a primary adjuvant treatment after surgery. Aromatase inhibitors (AIs) are widely administered to ER+ breast cancer patients as estrogen blockers; however, their safety remains controversial. The use of letrozole, an AI, has been reported to cause adverse cardiovascular effects. We aimed to elucidate the effects of letrozole on the cardiovascular system. Female rats exposed to letrozole for four weeks showed metabolic changes, i.e., decreased fatty acid oxidation, increased glycolysis, and hypertrophy in the left ventricle. Although lipid oxidation yields more ATP than carbohydrate metabolism, the latter predominates in the heart under pathological conditions. Reduced lipid metabolism is attributed to reduced ß-oxidation due to low circulating estrogen levels. In letrozole-treated rats, glycolysis levels were found to be increased in the heart. Furthermore, the levels of glycolytic enzymes were increased (in a high glucose medium) and the glycolytic rate was increased in vitro (H9c2 cells); the same was not true in the case of estrogen treatment. Reduced lipid metabolism and increased glycolysis can lower energy supply to the heart, resulting in predisposition to heart failure. These data suggest that a letrozole-induced cardiac metabolic remodeling, i.e., a shift from ß-oxidation to glycolysis, may induce cardiac structural remodeling.